Chapter 8 Drugs for Depression and Anxiety PDF

Drugs for depression and anxiety 1. Diagnosing depression and mood disorders Unipolar depression, or major depressive disorder, is diagnosed when people have a combination of the following symptoms for more than two weeks: Depressed mood (sadness - dysthymia). Difficulty concentrating or making de...

Drugs for depression and anxiety 1. Diagnosing depression and mood disorders Unipolar depression, or major depressive disorder, is diagnosed when people have a combination of the following symptoms for more than two weeks: Depressed mood (sadness - dysthymia). Difficulty concentrating or making decisions. Inability to experience pleasure in activities that were previously pleasurable (anhedonia), or decreased interest in pursuing those activities. Changes in sleep (excessive sleepiness or difficulty falling asleep). Changes in appetite (excessive eating or loss of appetite). Loss of energy/fatigue. Negative rumination and feelings of guilt or worthlessness. Suicidal thoughts. As you may have noticed, some of these same symptoms (lack of pleasure, difficulty concentrating, suicidal thoughts) occur in people with schizophrenia. There is also an overlap of some depression symptoms in people who have bipolar disorder. As we will discuss in greater detail in the next chapter, people with bipolar disorder alternate between periods of depressed mood and periods of mania, where mood is excessively elevated. It is important for physicians to distinguish between these disorders because the treatment is different for depression and bipolar disorder. In this chapter we focus on unipolar depression, which is also called major depressive disorder (MDD). Epidemiology of depression Depression has a lifetime occurrence of between 10-15% (depending on the study), which means that one out of every six to ten people will be diagnosed with depression at some point in their lives. Depression is the one of the biggest causes of disability according to the World Health Organization. This is because depression is a life-long condition that affects a substantial percentage of the population. The typical onset for MDD is early adulthood (20s) but can occur at any age. The occurrence of depression is higher in women than in men (by a factor of 2:1). However, men are 4 times more likely than women to take their lives by suicide. This raises the question of whether there is a biological basis for the sex difference in the prevalence of depression (like differences in sex hormones) or whether cultural factors like gender roles prevent men from being diagnosed and receiving treatment. Like several other brain diseases, depression is influenced by both genetic and environmental factors. The genetics of depression are complex, and the influence of genetics is less in depression than it is in schizophrenia and bipolar disorder. For example, the concordance of depression between identical twins is about 40%. There are no strong candidate genes. While there have been some associations between depression and certain gene variants, there are no genes that strongly predispose a person to develop depression. A major contributing factor to depression is psychological stress. Early childhood trauma (for example sexual or physical violence) increases the risk of developing depression. In women, depression can also be triggered by an abrupt decrease in estrogen levels, as occurs postpartum. In postpartum depression, the symptoms of depression persist long after the drop in estrogen occurs. It is thought that women who experience postpartum depression have a vulnerability to depression that is exacerbated by the drop in estrogen. Distinguishing depression from grief Grief is a normal human response to loss and shares many of the same features as depression. These include intense sadness, loss of appetite, difficulty sleeping, and a loss of pleasure in those things that normally bring pleasure. However, a deeply grieving person is still able to experience happiness intermittently, and they generally do not experience loss of self-esteem and feelings of worthlessness. Neither do they have suicidal thoughts. Because traumatic events can trigger depression in vulnerable individuals, it is important to consult a physician to help distinguish "normal grieving" from clinical depression. In these people, antidepressant medications treat depressive symptoms, but still allow the full range of feelings including sadness and grief. 2. Neurobiology of depression We now have a greater understanding that depression, anxiety, and related mood disorders are brain diseases, and not personality traits. What parts of the brain are affected in depression? As is the case with other psychiatric illnesses like schizophrenia, ADHD, and bipolar disorder, there is not a clear answer to this question. We have hypotheses about depression based on drugs that increase or decrease depressive symptoms, brain imaging studies, and genetics. The monoamine hypothesis of depression One hypothesis about the nature of depression is that it is caused by reduced levels of monoamine neurotransmitters, which are dopamine, norepinephrine, serotonin, and histamine. This idea arose from the observation that the drug reserpine (which was historically used to treat high blood pressure) induced a state of depression in people who were not previously depressed. Reserpine is a drug that lowers the levels of dopamine, norepinephrine, serotonin, and histamine. It does this by blocking the transporter that packages the neurotransmitters into vesicles so that they can be released when the neuron fires. When reserpine is administered, the monoamines are not put into the vesicles, and the neurons can't release neurotransmitter when they fire. Another piece of evidence that suggests serotonin levels might be low in people with depression is that symptoms of depression can be induced by eating a diet that lacks tryptophan. Tryptophan is the amino acid that is used to make serotonin, and it’s one of the essential amino acids that our body cannot synthesize; we need to eat foods with tryptophan to have the amino acid in our body. Since depression symptoms can be caused by tryptophan depletion, it is another piece of evidence that the serotonin system may not work properly in this disorder.  Figure 1. Neurons that release monoamines like serotonin, dopamine, and norepinephrine use a transporter called VMAT to package the neurotransmitters into vesicles. Reserpine is an antagonist of VMAT. When people are given reserpine their neurons cannot package serotonin, dopamine, and norepinephrine. Reserpine causes a state of depression that is relieved when the drug is no longer administered. Actions of serotonin Serotonin (also called 5HT) is similar to dopamine and norepinephrine in some respects. They are all synthesized from amino acids, and once they are released in the synapse they bind to G- protein coupled receptors to mediate their effects. The actions of serotonin (like DA and NE) are terminated by a transporter that recycles serotonin back into the presynaptic terminal for repackaging. Dopamine signals are terminated by DAT, norepinephrine signals are terminated by NET, and serotonin signals are terminated by SERT. Serotonin is associated with a number of important physiological functions. It regulates body temperature, vigilance, REM sleep induction, sexual desire and sexual functions, appetite and satiety. It also regulates mood. While dopamine is associated with feelings of euphoria, serotonin is associated with feelings of well-being and contentedness. Serotonin also influences sensory perception, and drugs that activate specific serotonin receptors can induce hallucinations and altered sensory perception. Serotonin neuron cell bodies are located in the midbrain and brainstem, and they send their axons throughout the brain. Newer hypotheses about depression Although there is a clear connection between serotonin and mood, it is not evident that this explains the cause, or etiology, of depression. In fact, antidepressant drugs will increase serotonin levels right away, but they don't treat the symptoms of depression for several weeks. So the reason why antidepressants work cannot be completely explained by serotonin. There is a relatively new idea that antidepressants work by increasing the number of synaptic connections in the cortex and hippocampus. These drugs have also been shown to increase neurogenesis, which is the generation of new neurons. Interestingly, imaging studies indicate that people with depression may have smaller hippocampus. The smaller volume of this brain structure could reflect a defect in neurogenesis that is improved with antidepressants. Another emerging idea about the cause of depression has to do with immune function and inflammation. This comes from observations that people with depression have elevated levels of inflammatory molecules called cytokines in their blood. Consistent with this, depression is a common side effect for cancer patients who are treated with the inflammatory cytokines interleukin-2 or interferon alpha. These drugs are used to treat melanoma and renal cell carcinoma and have many adverse effects. One of these side effects is depression, which resolves once the cytokine treatment stops. 3. Discovery of the first antidepressant medication The first antidepressant drug was discovered by accident, in a manner that was somewhat similar to the discovery of chlorpromazine for schizophrenia. The story is told very nicely in "Shrinks: The Untold Story of Psychiatry" by Dr. Jeffrey Lieberman. After chlorpromazine was discovered to help with schizophrenia, other drug companies saw the enormous profit that could be made treating schizophrenia. Companies in the 1950's were teaming up with psychiatrists to identify new antipsychotic drugs that could compete with chlorpromazine. A Swiss company called Geigy (which later became today's drug company Novartis) synthesized a panel of drugs that were based on the structure of chlorpromazine. They approached a Swiss psychiatrist named Ronald Kuhn to choose one of the 40 chemicals they had synthesized and give it to his schizophrenia patients. He chose one and found that it did not help his patients with schizophrenia. However, he decided (for reasons that are not clear) to give it to three of his patients who were institutionalized with depression. They had no benefit from one treatment with the drug, but he kept giving it to them (perhaps because antipsychotics took several weeks to take effect). Then, after about a week, his patients started improving and showing signs of hopefulness and improved mood. The drug was called imipramine, which would become the first antidepressant. Kuhn reported to Geigy that, while this wasn't a drug for schizophrenia, they potentially had a drug for depression, which was just as debilitating and lacked effective treatment. Astonishingly, Geigy was not interested in pursuing this, and kept looking for antipsychotics! Dr. Kuhn continued studying imipramine and tried to convince others to try this drug for their patients. Imipramine languished in obscurity until the wife of Robert Boehringer, an influential Giegy business partner, was diagnosed with depression. Since he was aware of Dr. Kuhn's discovery, Boehringer asked Dr. Kuhn to treat his wife. After witnessing his wife's remarkable improvement, he insisted that Geigy market the drug for depression. This was of course a windfall for the company, but more importantly THE breakthrough for the treatment of depression. It is difficult to know how long depression would have remained intractable without this series of serendipitous events. It should be emphasized that this breakthrough was not guided by our understanding of the neurobiology of depression. All of the drugs that came after are available thanks to a series of fortunate events. While antidepressants are indeed life-saving, they may not be the best treatments. As we learn more about depression (and anxiety), we may find other medicines that are more effective and may work more rapidly. 4. From serendipity to rational drug development Just as with schizophrenia, the discovery of imipramine led to the development of other drugs that were structurally similar. This first class of drugs is called tricyclic antidepressants based on their chemical structure. One of the most commonly used tricyclics today is amitriptyline. As techniques were developed to identify the receptors for the drugs, it became clear that these tricyclics all interacted with the serotonin transporter (called SERT) and the norepinephrine transporter (NET). Tricyclic antidepressants block these transporters, effectively increasing the amount of serotonin and norepinephrine in the synapse. They do not block the dopamine transporter, do not increase dopamine, and are not addictive. Tricyclics affect more than NET and SERT. They also block muscarinic acetylcholine receptors and histamine receptors, and they block some serotonin receptors and calcium channels. It is not clear whether these other targets of tricyclics contribute to their beneficial effect in depression, but they do contribute to their side effects. Tricyclics block muscarinic receptors, which are important for the "rest and digest" functions of the autonomic nervous system. Consequently, they cause side effects like dry eyes, nose and mouth, delayed digestion, constipation and urinary retention, and increased body temperature. Blockade of histamine receptors leads to their sedative and hypnotic effects. Their actions on calcium channels can cause heart arrhythmias and potential lethality with overdose. Today the most commonly prescribed antidepressants are those that have more selective actions on NET and SERT so that they avoid some of the potentially dangerous side effects of tricyclics. More recent antidepressants originated from the observation that tricyclics increased serotonin and norepinephrine levels. In 1987, the FDA approved a drug with selective effects on the serotonin transporter and without substantial activity at the other receptors for tricyclics. The drug, fluoxetine (trade name Prozac) was the first SSRI - a selective serotonin reuptake inhibitor. There are now several SSRIs that differ in their half-lives and their degree of selectivity. There are also SNRI's, which are serotonin/norepinephrine reuptake inhibitors. These are more similar to the original tricyclics, because they increase both serotonin and norepinephrine levels. Since SNRIs lack the effects on muscarinic, histamine receptors and calcium channels, they are safer than tricyclics in cases of overdose. An example of an SNRI is venlafaxine (Effexor). While SSRIs and SNRIs are considered safer than tricyclics, they are sometimes not effective, and studies indicate that tricyclics can help people who are not helped by SSRIs and SNRIs. Another challenge for the use of SSRIs and SNRIs is that they still have side effects that can be difficult for people to withstand. There are some side effects that subside after several days of use. Most notably, SSRIs cause stomach cramping and gastrointestinal pain. SSRIs also affect sleep and arousal. Interestingly these drugs cause some people to become sleepy and others to have difficulty falling asleep. Other side effects that generally subside include headaches, nausea, dizziness, and agitation. Some of the adverse effects of SSRIs do not subside with continued use and explain why some people stop taking their medication. SSRIs can affect different aspects of sexual behavior. They decrease interest in having sex (libido) and can cause difficulties in having an erection or orgasm. In addition, SSRIs can cause significant weight gain. This effect seems to be more prominent for specific SSRIs, with the drug paroxetine most associated with weight gain. Finally, they can increase the occurrence of migraine headaches for those people who have a migraine condition. Figure 2. Mechanism of action of Selective Serotonin Reuptake Inhibitors. SSRIs are antagonists of the serotonin transporter. The diagram on the left illustrates how serotonin is rapidly removed from the synapse by the serotonin transporter (SERT). Because of this rapid clearance there is only one receptor that is activated. When SSRIs are administered, there is no clearance of serotonin, and the neurotransmitter stays in the synapse. Consequently, more serotonin receptors are activated. 5. New investigational treatments for depression There is a pressing need for better antidepressants, and several new classes of medication are in clinical trials. One drug that is currently in clinical trials is ketamine. Ketamine has been used for many years as an anesthetic in children and in veterinary practice. However, it isn't used as an anesthetic in adults because it can cause hallucinations. In fact, ketamine has been used recreationally as a hallucinogen and has been used by scientists as a drug that induces "schizophrenia-like" symptoms. Although ketamine does act on a few receptors in the brain, it is most widely known as an NMDA receptor antagonist. Therefore, the finding that ketamine has antidepressant properties has been surprising and somewhat controversial. The original studies by Carlos Zarate reported that ketamine delivered intravenously provided rapid relief from depression and suicidal ideation. Within 45 minutes of infusion, patients reported improved mood that lasted for one to two weeks. Current clinical trials are underway to determine whether it can be administered by other routes than IV, and to determine whether it can be used as a long-term treatment of depression. A recent clinical trial where ketamine was taken by nasal spray was stopped after patients reported hallucinations. The newest class of antidepressants that are being investigated are hallucinogens that act on the serotonin system. The recreational drugs MDMA (Ecstasy), LSD, and psilocybin have all shown promising results in early clinical trials where they have been used to treat end-of-life depression in cancer patients and post-traumatic stress disorder. MDMA acts in a mechanism that is similar to amphetamine, but it is more selective for serotonin. Whereas amphetamine causes the reverse transport of dopamine, norepinephrine, and serotonin, MDMA primarily causes the reverse transport of serotonin. LSD and psilocybin are both agonists of serotonin receptors. They often cause nausea and vomiting as side effects and do not have abuse liability. Effective results are obtained when the hallucinogens are administered by a psychiatrist or clinical psychologist who guides the patient through the hallucinogenic experience. These drugs can have different effects depending on the psychological state of the person taking them. Therefore, the therapeutic regimen considers things like the environment (lighting, music, wall art) and words that are used during the session (reminding the patient that they are in a safe place). 6. Other uses for antidepressants Although antidepressants were developed and tested for their ability to treat depression, they are also first-line treatments for a number of other conditions. Antidepressants have been shown to be effective for the treatment of several anxiety disorders, including generalized anxiety, post-traumatic stress disorder, obsessive compulsive disorder, and phobias. In terms of the number of people who respond to medication, SSRIs are more effective at treating anxiety than they are at treating depression. These two mood disorders are often comorbid, and there may be shared etiology between depression and anxiety. SSRIs are also used to effectively treat some eating disorders, and to treat chronic (neuropathic) pain. Tricyclic antidepressants are also effective in the treatment of chronic pain and may in fact be more effective than SSRIs. References Jeffrey Lieberman (2015) Shrinks: The Untold Story of Psychiatry Douglas Levinson (2005) "The genetics of depression: a review" Biological Psychiatry